Ho, Hei Ming Kenneth; (2022) Developing Drug-loaded Nanogel Formulations for Intrapericardial Delivery. Doctoral thesis (Ph.D), UCL (University College London).

Text Hei Ming Kenneth Ho 17115421 Thesis final.pdf - Other Access restricted to UCL open access staff until 1 August 2025. Download (15MB)

Abstract

Intrapericardial delivery is a novel route for administering localised therapy to the heart and offers advantageous pharmacokinetic profiles. Although concerns exist about invasiveness and associated complications these can be mitigated using minimally invasive techniques; however, it requires further consideration regarding the formulation of the drug being delivered for it to pass through small-bore delivery devices. Therefore, the research presented in this thesis aimed to investigate the development of nanogel formulations for use in minimally invasive intrapericardial delivery. Propranolol-loaded chitosan-TPP nanogels were first evaluated to understand the predictability of nanogel properties. The prediction models were applied with structurally similar drugs. Relationships were found between molecular descriptors and performance parameters. Hence, the encapsulation and formation processes were drug-dependent and not simply incorporated into inter-chain voids. Moreover, the processing factors in the fabrication significantly affected the nanogels properties, which demonstrated that the scaling-up of the fabrication process is not simply via increasing the volume pro-rata. Assessment of the cytotoxicity of propranolol on epicardial cells, fibroblasts, and cardiomyoblasts revealed that propranolol is not a suitable model drug for intrapericardial delivery. Moreover, higher cytotoxic sensitivity to propranolol was observed with epicardial cells, which highlighted the importance of using epicardial cells in cell viability tests rather than more generic cell types when modelling intrapericardial drug delivery during the screening of drug formulations. Further candidate nanogel formulations were investigated including a novel CS-GAA formulation produced at a more basic pH than the conventional chitosan-TPP nanogels (pH 4.5), which enabled the loading of the antifibrotic peptide Ac-SDKP. To quantify the peptide, it was necessary to establish an HPLC-UV assay. Unfortunately, the peptide released from the nanogels was not detectable after 24 hours during the release study conducted, of which the degradation of the peptide was likely promoted by the phosphate buffer saline. Conversely, the nanogels formulation reduced the peptide concentration needed to suppress the metabolic activity of fibroblasts in the presence of TGF-β1. In conclusion, the research reported shows the technical feasibility of producing nanogels loaded with peptide drugs, with Ac-SDKP-loaded nanogels offering several attributes that make them potentially ideally suited for intrapericardial delivery for treating heart disease.

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